[Recent findings on nitrates: their action, bioactivation and development of tolerance].
Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.
Münzel
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Medizinische Klinik für Kardiologie, Angiologie und internistische Intensivmedizin, Johannes Gutenberg Universität Mainz. tmuenzel@uni-mainz.de
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D003327:Coronary Disease / Q000188:drug therapy*; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D008981:Molsidomine / Q000494:pharmacology / Q000627:therapeutic use; D009566:Nitrates / Q000494:pharmacology* / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D005996:Nitroglycerin / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress; D010417:Pentaerythritol Tetranitrate / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D009566:Nitrates; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D010417:Pentaerythritol Tetranitrate; D006830:Hydralazine; D009569:Nitric Oxide; D008981:Molsidomine; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate